Antibody (Ab) responses induced by endemic human coronaviruses (HCoVs) may affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific Ab production due to cross-reactivity among these HCoVs. To explore this hypothesis, we collected serum samples of healthy healthcare workers (HCW) at four time-points: pre-vaccination, post-vaccination (1st and 2nd dose) and 6 months post-vaccination. We used N protein peptide-based enzyme-linked immunosorbent assays (ELISA) specific for alphaCoVs (NL63 and 229E) and betaCoVs (OC43 and HKU1) as well as N and S peptide-based ELISA for SARS-CoV-2. Low levels of SARS-CoV-2 N protein-specific Abs were present in some individuals prior to vaccination. The level remained constant following one or two doses of vaccine and declined after 6 months. SARS-CoV-2 S protein-specific Abs level were low in most individuals prior to vaccination, increased sharply following 1st and 2nd vaccinations and declined by 6 months.

We observed low levels of pre-existing IgG Abs against endemic HCoVs prior to COVID-19 vaccination. However, like SARS-CoV-2-specific IgG Ab titers, they increased (1.6–1.9-fold) following SARS-CoV-2 vaccination and waned 6 months later. IgG Abs surge targeting HCoV N protein suggest polyclonal activation of memory B cell responses induced by the S gene based COVID-19 vaccines. The levels of IgG Abs against endemic HCoVs were 1.1–1.5 times higher in SARS-CoV-2 seropositive vs. seronegative individuals, suggesting serological cross-reactivity between SARS-CoV-2 and other HCoVs. In summary, short-term immunity (six months) against common cold causing HCoVs can be reactivated following COVID-19 vaccination however it requires booster dose for long term protection.